Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Sakai, Osaka, Japan.
Biomaterials. 2010 Sep;31(27):7096-105. doi: 10.1016/j.biomaterials.2010.05.045. Epub 2010 Jun 30.
Recently, we showed that incorporation of poly[2-(2-ethoxy)ethoxyethyl vinyl ether (EOEOVE)], which exhibits a lower critical solution temperature around 40 degrees C, provides temperature-sensitive properties to stable liposomes. In this study, we applied this thermosensitive polymer for preparation of temperature-sensitive liposomes for tumor-specific chemotherapy with doxorubicin (DOX). We prepared liposomes consisting of PEG-lipid, egg yolk phosphatidylcholine, cholesterol and copoly(EOEOVE-block-octadecyl vinyl ether), which was synthesized as poly(EOEOVE) having anchors for fixation onto liposome membrane. The copolymer-incorporated liposomes were stable and retained DOX in their inside below physiological temperatures. However, they exhibited a significant release of encapsulated DOX above 40 degrees C and released DOX almost completely within 1 min at 45 degrees C. The copolymer-modified liposomes exhibited a long circulating property and biodistribution similar to that of PEG-modified liposomes. The copolymer-modified liposomes loaded with DOX were injected intravenously into tumor-bearing mice. Tumor growth was strongly suppressed when the tumor site was heated to 45 degrees C for 10 min at 6-12 h after injection. However, injection of the liposomes exhibited only slight tumor-suppressive effects as long as mild heating was not applied to the target site. The highly temperature-sensitive properties of the copolymer-incorporated liposomes might contribute to establishment of tumor-selective and effective chemotherapy.
最近，我们发现，聚[2-(2-乙氧基)乙氧基乙基乙烯基醚]（EOEOVE）的掺入可赋予稳定脂质体温度敏感性，该聚合物的最低临界溶解温度约为 40°C。在这项研究中，我们将这种温敏聚合物应用于制备载多柔比星（DOX）的热敏脂质体，以实现肿瘤特异性化疗。我们制备了由 PEG-脂质、蛋黄卵磷脂、胆固醇和共聚物（EOEOVE-嵌段-十八烷基乙烯基醚）组成的脂质体，该共聚物通过与脂质体膜结合的固定锚合成，具有温敏性。共聚物掺入的脂质体在生理温度以下稳定，并将 DOX 保留在其内部。然而，当温度高于 40°C 时，共聚物修饰的脂质体表现出明显的 DOX 释放，在 45°C 下 1 分钟内几乎完全释放 DOX。与 PEG 修饰的脂质体相比，共聚物修饰的脂质体具有长循环特性和相似的生物分布。将载 DOX 的共聚物修饰的脂质体静脉注射到荷瘤小鼠中。在注射后 6-12 小时，将肿瘤部位加热至 45°C 10 分钟，可强烈抑制肿瘤生长。然而，只要不对靶部位进行温和加热，脂质体注射仅表现出轻微的肿瘤抑制作用。共聚物掺入的脂质体具有高度的温度敏感性，可能有助于建立肿瘤选择性和有效的化疗方法。
